H Jörnvall

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (708)2675.63 Total impact

  • Michael Landreh, Hans Jörnvall
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    ABSTRACT: The proinsulin C-peptide has molecular, cellular and organismal activities but lacks disease-associated mutations or short-term loss-of-function effects. This dilemma between activity and function may be explained from its evolutionary setting with insulin as an ancestral partner. The charge, approximate length and flexibility of C-peptide are all that is required for the insulin interactions, while remaining aspects are free to evolve, where new bioactivities can emerge. They can initially be transient, weak, and non-functional, but may gradually be consolidated. In this manner, C-peptide may have acquired multiple bioactivities, explaining why some yet have limited functions but could represent early-stage hormonal-like activities. Copyright © 2015. Published by Elsevier B.V.
    FEBS Letters 01/2015; 589(4). DOI:10.1016/j.febslet.2015.01.006 · 3.34 Impact Factor
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    ABSTRACT: STUDY QUESTION: Is it possible to derive a scaffold from human testis for the purpose of tissue engineering and regenerative medicine? SUMMARY ANSWER: We developed a method to produce a cytocompatible decellularized testicular matrix (DTM) while maintaining the native tissue-specific characteristics and components. WHAT IS KNOWN ALREADY: The potential benefits of tissue-specific scaffolds consisting of naturally-derived extracellular matrix (ECM) have been demonstrated using a wide variety of animal and human tissue sources. However, so far, testis scaffolds have never been considered for constructive remodelling purposes. STUDY DESIGN, SIZE, DURATION: Human cadaveric testicular tissue was exposed for 24 or 48 h to 1% Triton X-100 and/or 1% sodium dodecyl sulphate (SDS). Acellular samples were used for further scaffold characterization purposes. PARTICIPANTS/MATERIALS, SETTING, METHODS: The extent of decellularization was evaluated by histology. Confirmation of cell removal in DTM was done by a DNA quantification technique. Retention of testicular tissue-specific characteristics was evaluated by mass spectrometry, immunohistochemistry, Alcian blue staining and scanning electron microscopy. Soluble toxicity and testicular cell attachment was assessed to check the cytocompatibility of DTM scaffolds. MAIN RESULTS AND THE ROLE OF CHANCE: Histological analysis showed that DTM could be obtained by mechanical agitation in 1% SDS for 24 h. The resulting DTM was found to be clear of cells while retaining the typical three-dimensional structure and the major components of the native tissue scaffold, including collagen type I and IV, fibronectin, laminin and glycosaminoglycans. In addition, using proteomic analysis, we revealed numerous additional ECM proteins in DTM, indicating its complex nature. The mass spectrometry data were deposited to the ProteomeXchange with identifier PXD001524. Importantly, we demonstrated that DTM scaffolds are not cytotoxic, as evidenced by MTT assay not showing an aberrant fibroblast proliferation activity after indirect exposure, and support testicular cell attachment and infiltration. LIMITATIONS, REASONS FOR CAUTION: The functionality of human testicular cells in DTM needs to be investigated. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that the insights into the molecular composition of the testicular ECM provide new clues for the unravelling of its important yet poorly understood role in regulating testicular function, and DTM-based bioscaffolds are promising components for the development of human in vitro spermatogenesis as a treatment for various types of male fertility disorders. STUDY FUNDING/COMPETING INTERESTS: This study is supported by a Ph.D. grant from the Agency for Innovation by Science and Technology (IWT) and research grants from the Flemish League Against Cancer-Public Utility Foundation (VLK), the Scientific Research Foundation Flanders (FWO), the Vrije Universiteit Brussel, the Swedish Research Council/ Finnish Academy of Science, Emil och Wera Cornells Stiftelse, the Swedish Childhood Cancer Foundation as well as through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. J.-B.S. was supported by the German Research Foundation (DFG-Grant No.: STU 506/3-1). E.G. and J.D.K. are postdoctoral fellows of the Scientific Research Foundation Flanders. The authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: Not applicable.
    Human Reproduction 11/2014; 30(2). DOI:10.1093/humrep/deu330 · 4.59 Impact Factor
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    ABSTRACT: Molecular research on ADH since ∼50 years.•Updates on numbers of known ADH, MDR and SDR forms.•Constant and variable forms, with apparent restrictions also in some “silent” forms.•Altered eras of research but continued overall increases in data collections.
    Chemico-Biological Interactions 10/2014; DOI:10.1016/j.cbi.2014.10.017 · 2.98 Impact Factor
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    ABSTRACT: Spider silk fibers are produced from soluble proteins (spidroins) under ambient conditions in a complex but poorly understood process. Spidroins are highly repetitive in sequence but capped by nonrepetitive N- and C-terminal domains (NT and CT) that are suggested to regulate fiber conversion in similar manners. By using ion selective microelectrodes we found that the pH gradient in the silk gland is much broader than previously known. Surprisingly, the terminal domains respond in opposite ways when pH is decreased from 7 to 5: Urea denaturation and temperature stability assays show that NT dimers get significantly stabilized and then lock the spidroins into multimers, whereas CT on the other hand is destabilized and unfolds into ThT-positive β-sheet amyloid fibrils, which can trigger fiber formation. There is a high carbon dioxide pressure (pCO2) in distal parts of the gland, and a CO2 analogue interacts with buried regions in CT as determined by nuclear magnetic resonance (NMR) spectroscopy. Activity staining of histological sections and inhibition experiments reveal that the pH gradient is created by carbonic anhydrase. Carbonic anhydrase activity emerges in the same region of the gland as the opposite effects on NT and CT stability occur. These synchronous events suggest a novel CO2 and proton-dependent lock and trigger mechanism of spider silk formation.
    PLoS Biology 08/2014; 12(8):e1001921. DOI:10.1371/journal.pbio.1001921 · 11.77 Impact Factor
  • Michael Landreh, Linus J Ostberg, Hans Jörnvall
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    ABSTRACT: The C-peptide of proinsulin exhibits multiple activities and several of the underlying molecular interactions are known. We recently showed that human C-peptide is sub-divided into a tripartite architecture and that the pattern, rather than the exact residue positions, is a characteristic feature. We have now analyzed 75 proinsulins, ranging from fish to human and find a limited co-evolution with insulin, but with many marked deviations. This suggests a complex relationship, in which not only insulin affects the evolution of C-peptide. A subdivided nature, however, is a characteristic feature among all C-peptides, with the N-terminal segment the one most conserved. This segment, ascribed chaperoning charge-interactions with insulin, suggests that the insulin interactions constitute a basic function, although largely shifting from Glu to Asp residues in C-peptides of lower life forms. A second conserved feature is a mid-segment with a high content of adjacent Pro and Gly residues, in mammalian C-peptides compatible with a turn structure, but with fewer and more distantly interspaced such residues in the non-mammalian forms, and even absent in several fish forms. However, this segment of coelacanth C-peptide possesses a unique Cys distribution, capable of forming a disulfide-stabilized turn. Finally, the C-terminal segment of mammalian C-peptides, ascribed a possible receptor-interacting function, is not really discernable in the sub-mammalian forms. Combined, these patterns suggest an evolutionary stepwise acquisition of the tripartite mammalian C-peptide molecule, with insulin-interaction being ancestral, various turn stabilizations apparently of intermediate emergence, and possible receptor-interaction the most recent addition.
    Biochemical and Biophysical Research Communications 07/2014; 450(4). DOI:10.1016/j.bbrc.2014.07.012 · 2.28 Impact Factor
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    ABSTRACT: Abstract Aggregation of transthyretin (TTR), a plasma-binding protein for thyroxine and retinol-binding protein, is the cause of several amyloid diseases. Disease-associated mutations are well known, but wild-type TTR is, to a lesser extent, also amyloidogenic. Monomerization, not oligomer formation as in several other depository diseases, is the rate-limiting step in TTR aggregation, and stabilization of the natively tetrameric form can inhibit amyloid formation. Modifications on Cys10, as well as interactions with native ligands in plasma, were early found to influence the equilibrium between tetrameric and monomeric TTR by dissociating or stabilizing the tetramer. Following these discoveries, synthetic ligands for pharmacological prevention of TTR aggregation could be developed. In this article, we outline how the different types of TTR interactions and its microheterogeneity in plasma are related to its propensity to form amyloid fibrils. We conclude that plasma constituents and dietary components may act as natural TTR stabilizers whose mechanisms of action provide cues for the amelioration of TTR amyloid disease.
    Biomolecular concepts 06/2014; 5(3):257-64. DOI:10.1515/bmc-2014-0006
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    ABSTRACT: Abstract Many biological roles have been assigned to proinsulin C-peptide over the years. Some appear surprisingly disparate and sometimes even contradictory, like chaperone-like actions and depository tendencies. This review summarizes recently reported biomolecular interactions of the peptide and presents how they correlate with structural and functional aspects into a partitioned molecular architecture. At the structural level, the C-peptide sequence and fold can be subdivided into three distinct parts ('tripartite'). At the functional level, its chaperone-like abilities, self-assembly, and membrane interactions, as well as interactions with relevant proteins can be separately ascribed to these three segments. At the biological level, the assignments are compatible with the suggested roles of C-peptide in granular insulin storage, chaperone-like activities on insulin oligomers, possible depository tendencies, and proposed receptor interactions. Finally, the assignments give interesting parallels to further bioactive peptides, including glucagon and neurotensin. Provided pharmaceutical and clinical trials are successfully completed, the present interpretations should supply mechanistic explanations on C-peptide as a bioactive compound of importance in health and diabetes.
    Biomolecular concepts 05/2014; 5(2):109-18. DOI:10.1515/bmc-2014-0005
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    Michael Landreh, Jan Johansson, Hans Jörnvall
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    ABSTRACT: Figure optionsDownload full-size imageDownload high-quality image (141 K)Download as PowerPoint slide
    Journal of Molecular Biology 05/2014; DOI:10.1016/j.jmb.2014.03.005 · 3.91 Impact Factor
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    ABSTRACT: An 84-residue bactericidal peptide, PSK, was purified from a Chrysomya megacephala fly larvae preparation. Its amino acid sequence is similar to that of a previously reported larval peptide of the Drosophila genus (SK84) noticed for its anticancer and antimicrobial properties. The PSK sequence is also homologous to mitochondrial ATPase inhibitors from insects to humans (35-65% sequence identity), indicating an intracellular protein target and possible mechanism for PSK. It contains a cluster of six glycine residues, and has several two- and three-residue repeats. It is active against both Gram-positive and Gram-negative bacteria via a mechanism apparently involving cell membrane disintegration and inhibition of ATP hydrolysis. In addition, PSK induces an inward cationic current in pancreatic β cells. Together, the findings identify a bioactive peptide of the ATPase inhibitor family with specific effects on both prokaryotic and mammalian cells.
    Biochemical and Biophysical Research Communications 03/2014; DOI:10.1016/j.bbrc.2014.02.138 · 2.28 Impact Factor
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    ABSTRACT: The mechanisms controlling the conversion of spider silk proteins into insoluble fibres, which happens in a fraction of a second and in a defined region of the silk glands, are still unresolved. The N-terminal domain changes conformation and forms a homodimer when pH is lowered from 7 to 6; however, the molecular details still remain to be determined. Here we investigate site-directed mutants of the N-terminal domain from Euprosthenops australis major ampullate spidroin 1 and find that the charged residues D40, R60 and K65 mediate intersubunit electrostatic interactions. Protonation of E79 and E119 is required for structural conversions of the subunits into a dimer conformation, and subsequent protonation of E84 around pH 5.7 leads to the formation of a fully stable dimer. These residues are highly conserved, indicating that the now proposed three-step mechanism prevents premature aggregation of spidroins and enables fast formation of spider silk fibres in general.
    Nature Communications 02/2014; 5:3254. DOI:10.1038/ncomms4254 · 10.74 Impact Factor
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    ABSTRACT: Insulin, islet amyloid polypeptide (IAPP), and the C-peptide part of proinsulin are co-secreted from the pancreatic beta cell granules. IAPP aggregation can be inhibited by insulin and insulin aggregation by C-peptide, but different binding and disaggregating interactions may apply for the peptide complexes. A more detailed knowledge of these interactions is necessary for the development strategies against diabetic complications that stem from peptide aggregations. Mass spectrometry (MS) is utilized to investigate pH-dependencies, sequence determinants and association strengths of interactions between pairs of all three peptides. Electrospray ionization (ESI)-MS was used to monitor complex formation and interaction stoichiometries at different pH values. Collision-induced dissociation (CID) was employed to probe relative association strengths and complex dissociation pathways. IAPP, like C-peptide, removes insulin oligomers observable by ESI-MS. Both C-peptide and IAPP form stable 1:1 heterodimers with insulin. Complexes of the negatively charged C-peptide with the positively charged IAPP, on the other hand, are easily dissociated. Replacement of the conserved glutamic acid residues in C-peptide with alanine residues increases the stability, indicating that net charge alone does not predict association strength. Binding to insulin has been suggested to stabilize a helical fold in IAPP via charge and hydrophobic interactions, which is in agreement with the now observed high gas-phase stability and sensitivity to low pH. Combined, these results suggest that the C-peptide-insulin and IAPP-insulin interactions are mediated by a defined binding site, while such a feature is not apparent in the IAPP-C-peptide association. Hence, IAPP and C-peptide are interacting in similar manners and with similar monomerizing effects on insulin, suggesting that both peptides can prevent insulin aggregation. Simultaneous interactions of all three peptides cannot be excluded but appear unlikely from the uneven pairwise binding strengths. Copyright © 2013 John Wiley & Sons, Ltd.
    Rapid Communications in Mass Spectrometry 01/2014; 28(2):178-84. DOI:10.1002/rcm.6772 · 2.51 Impact Factor
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    ABSTRACT: Chromosomal aneuploidy has been identified as a prognostic factor in the majority of sporadic carcinomas. However, it is not known how chromosomal aneuploidy affects chromosome-specific protein expression in particular, and the cellular proteome equilibrium in general. The aim was to detect chromosomal aneuploidy-associated expression changes in cell clones carrying trisomies found in colorectal cancer. We used microcell-mediated chromosomal transfer to generate three artificial trisomic cell clones of the karyotypically stable, diploid, yet mismatch-deficient, colorectal cancer cell line DLD1 - each of them harboring one extra copy of either chromosome 3, 7 or 13. Protein expression differences were assessed by two-dimensional gel electrophoresis and mass spectrometry, compared to whole-genome gene expression data, and evaluated by PANTHER classification system and Ingenuity Pathway Analysis (IPA). In total, 79 differentially expressed proteins were identified between the trisomic clones and the parental cell line. Up-regulation of PCNA and HMGB1 as well as down-regulation of IDH3A and PSMB3 were revealed as trisomy-associated alterations involved in regulating genome stability. These results show that trisomies affect the expression of genes and proteins that are not necessarily located on the trisomic chromosome, but reflect a pathway-related alteration of the cellular equilibrium.
    Analytical cellular pathology (Amsterdam) 01/2014; 36(5-6). DOI:10.3233/ACP-140088 · 1.76 Impact Factor
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    ABSTRACT: Abstract Context: Biological material reflecting the in vivo composition of markers provides a high potential for biomarker discovery. Objective: We compared the serum proteome following heat- and nitrogen-preservation, with and without subsequent storage at room temperature. Materials and methods: Serum samples were collected, treated and analysed by two-dimensional gel electrophoresis. Protein spots were identified and confirmed by two mass spectrometry approaches (MALDI & ESI) and subjected to Ingenuity Pathway Analysis. Results: We revealed 24 differentially expressed proteins (p ≤ 0.05) between nitrogen and heat preservation, and 87 between nitrogen and heat preservation with subsequent storage for 120 h at room-temperature. Mass spectrometry identified 25 polypeptides. Pathway analysis resulted in networks maintaining Cellular Assembly and Organization, Movement and Maintenance. Conclusion: Heat-stabilization does not substantially change the short-term proteome composition of serum compared with nitrogen treatment. However, heat-stabilization alone seems insufficient for long-term sample preservation for serum samples. We identified transthyretin and apolipoprotein A-IV as sample quality markers.
    Archives of Physiology and Biochemistry 07/2013; DOI:10.3109/13813455.2013.806556
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    ABSTRACT: Glomerular diseases represent major diagnostic and therapeutic challenges with classification of these diseases largely relying on clinical and histological findings. Elucidation of molecular mechanisms of progressive glomerular disease could facilitate quicker development. High-throughput expression profiling reveals all genes and proteins expressed in tissue and cell samples. These methods are very appropriate for glomerular disease as pure glomeruli can be obtained from kidney biopsies. To date, proteome profiling data are only available for normal glomeruli, but more robust transcriptome methods have been applied to many mouse model and a few human glomerular diseases. Here, we have carried out a meta-analysis of currently available glomerular expression data in normal and diseased glomeruli from mice, rats, and humans using a standardized protocol. The results suggest a potential for glomerular transcriptomics in identifying pathogenic pathways, disease monitoring, and the feasibility to use animal models to study human glomerular disease. We also found that currently there are no specific consensus biomarkers or pathways among different disease data sets, indicating there are likely disease-specific mechanisms and expression profiles. Thus, further transcriptomics and proteomics analysis, especially that of dynamic changes in the diseases, may lead to novel diagnostics tools and specific pharmacologic therapies.Kidney International advance online publication, 19 June 2013; doi:10.1038/ki.2013.169.
    Kidney International 06/2013; 84(3). DOI:10.1038/ki.2013.169 · 8.52 Impact Factor
  • M Landreh, J Johansson, H Jörnvall
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    ABSTRACT: Gradually, the C-peptide part of proinsulin has evolved from being viewed upon as a side product of insulin synthesis and secretion to being considered as a bioactive peptide with endocrine functions. Independent of these, its biophysical properties and peptide interactions point to still further roles of C-peptide, in particular regarding possible links to diabetes-related protein aggregations. Insulin, which can deposit at the injection sites in the treatment of diabetes, and islet amyloid polypeptide (IAPP), which can form amyloid fibrils in the islets of Langerhans in diabetes type 2, are kept nonaggregated by charge-based interactions with C-peptide at defined stoichiometries. It is possible that the conformational stabilization of insulin and IAPP by C-peptide may also counterbalance their aggregational tendencies at the high peptide concentrations in the pancreatic β-cell secretory granules. The concentration imbalances of C-peptide, insulin, and IAPP from the hyperpeptidism early in T2DM patients and the insulin-only injections in T1DM patients may distort equilibria of these peptide interactions and promote protein aggregation. Additionally, the chaperone-like actions of C-peptide may increase bioavailability of insulin supplements given to T1DM patients and prevent the formation of insulin deposits. Similarly, peptide interactions may influence depository tendencies in additional peptide systems. In short, biophysical studies are relevant to establish all roles of peptide imbalances in T1DM and T2DM and associated depository diseases.
    Hormone and Metabolic Research 06/2013; 45(11). DOI:10.1055/s-0033-1347208 · 2.15 Impact Factor
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    ABSTRACT: Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs) and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP) that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant.
    PLoS ONE 01/2013; 8(1):e53876. DOI:10.1371/journal.pone.0053876 · 3.53 Impact Factor
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    ABSTRACT: Different lines of alcohol dehydrogenases (ADHs) have separate superfamily origins, already recognized but now extended and re-evaluated by re-screening of the latest databank update. The short-chain form (SDR) is still the superfamily with most abundant occurrence, most multiple divergence, most prokaryotic emphasis, and most non-complicated architecture. This pattern is compatible with an early appearance at the time of the emergence of prokaryotic cellular life. The medium-chain form (MDR) is also old but second in terms of all the parameters above, and therefore compatible with a second emergence. However, this step appears seemingly earlier than previously considered, and may indicate sub-stages of early emergences at the increased resolution available from the now greater number of data entries. The Zn-MDR origin constitutes a third stage, possibly compatible with the transition to oxidative conditions on earth. Within all these three lines, repeated enzymogeneses gave the present divergence. MDR-ADH origin(s), at a fourth stage, may also be further resolved in multiple or extended modes, but the classical liver MDR-ADH of the liver type can still be traced to a gene duplication ∼550 MYA (million years ago), at the early vertebrate radiation, compatible with the post-eon-shift, "Cambrian explosion". Classes and isozymes correspond to subsequent and recent duplicatory events, respectively. They illustrate a peculiar pattern with functional and emerging evolutionary distinctions between parent and emerging lines, suggesting a parallelism between duplicatory and mutational events, now also visible at separate sub-stages. Combined, all forms show distinctive patterns at different levels and illustrate correlations with global events. They further show that simple molecular observations on patterns, multiplicities and occurrence give much information, suggesting common divergence rules not much disturbed by horizontal gene transfers after the initial origins.
    Chemico-biological interactions 11/2012; DOI:10.1016/j.cbi.2012.11.008 · 2.46 Impact Factor
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    ABSTRACT: Proinsulin processing into insulin and C-peptide in the secretory granules of the pancreatic β-cells occurs under mildly acidic conditions and at high peptide concentrations (>10 mM). Mature insulin has reduced solubility and a propensity to adopt an amyloid-like structure, but is physiologically released as a mixture of a zinc-containing core and a zinc-free, C-peptide-rich fluid phase. C-peptide is known to function in the insulin secretion, but its exact mode of interaction is non-established. We now demonstrate that C-peptide in sub-stoichiometric amount versus insulin co-precipitates with insulin at the pH found in secretory vesicles. Precipitation is reversible and the precipitate is dissolved by elevation of the pH. This effect was found to be dependent on relatively conserved glutamate residues in the otherwise poorly conserved C-peptide. Together, the data show that C-peptide has the ability to influence insulin solubility. The physiological pH changes between insulin processing and release sites may therefore affect the quaternary structure of insulin, as well as the phase transitions during insulin sorting and secretion. © 2012 The Authors Journal compilation © 2012 FEBS.
    FEBS Journal 10/2012; DOI:10.1111/febs.12045 · 3.99 Impact Factor
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    ABSTRACT: The assembly of proteins into amyloid fibrils can be an element of both protein aggregation diseases and a functional unit in healthy biological pathways. In both cases, it must be kept under tight control to prevent undesired aggregation. In normophysiology, proteins can self-chaperone amyloidogenic segments by restricting their conformational flexibility in an overall stabilizing protein fold. However, some aggregation-prone segments cannot be controlled in this manner and require additional regulatory elements to limit fibrillation. The present review summarizes different molecular mechanisms that proteins use to control their own assembly into fibrils, such as the inclusion of a chaperoning domain or a blocking segment in the proform, the controlled release of an amyloidogenic region from the folded protein, or the adjustment of fibrillation propensity according to pH. Autoregulatory elements can control disease-related as well as functional fibrillar protein assemblies and distinguish a group of self-regulating amyloids across a wide range of biological functions and organisms.
    Biochemical Journal 10/2012; 447(2):185-92. DOI:10.1042/BJ20120919 · 4.78 Impact Factor
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    ABSTRACT: Formation of spider silk from its constituent proteins-spidroins-involves changes from soluble helical/coil conformations to insoluble β-sheet aggregates. This conversion needs to be regulated to avoid precocious aggregation proximally in the silk gland while still allowing rapid silk assembly in the distal parts. Lowering of pH from about 7 to 6 is apparently important for silk formation. The spidroin N-terminal domain (NT) undergoes stable dimerization and structural changes in this pH region, but the underlying mechanisms are incompletely understood. Here, we determine the NMR and crystal structures of Euprosthenops australis NT mutated in the dimer interface (A72R). Also, the NMR structure of wild-type (wt) E. australis NT at pH7.2 and 300 mM sodium chloride was determined. The wt NT and A72R structures are monomers and virtually identical, but they differ from the subunit structure of dimeric wt NT mainly by having a tryptophan (W10) buried between helix 1 and helix 3, while W10 is surface exposed in the dimer. Wedging of the W10 side chain in monomeric NT tilts helix 3 approximately 5-6Å into a position that is incompatible with that of the observed dimer structure. The structural differences between monomeric and dimeric NT domains explain the tryptophan fluorescence patterns of NT at pH7 and pH6 and indicate that the biological function of NT depends on conversion between the two conformations.
    Journal of Molecular Biology 06/2012; 422(4):477-87. DOI:10.1016/j.jmb.2012.06.004 · 3.91 Impact Factor

Publication Stats

26k Citations
2,675.63 Total Impact Points

Institutions

  • 1973–2014
    • Karolinska Institutet
      • • Department of Medical Biochemistry and Biophysics
      • • Institutionen för onkologi-patologi
      • • Department of Medicine, Huddinge
      Solna, Stockholm, Sweden
  • 2012
    • Latvian Institute of Organic Synthesis
      Rija, Rīga, Latvia
  • 1984–2012
    • Swedish University of Agricultural Sciences
      • • Institutionen för anatomi, fysiologi och biokemi
      • • Institutionen för molekylärbiologi
      Uppsala, Uppsala, Sweden
    • Universität Stuttgart
      • Institute of Organic Chemistry
      Stuttgart, Baden-Wuerttemberg, Germany
  • 2003–2010
    • Linköping University
      Linköping, Östergötland, Sweden
  • 2007
    • Huazhong University of Science and Technology
      • School of Life Science and Technology
      Wuhan, Hubei, China
    • University Hospital Linköping
      Linköping, Östergötland, Sweden
  • 2002–2005
    • Tallinn University of Technology
      • Department of Gene Technology
      Tallinn, Harjumaa, Estonia
  • 1987–2005
    • Karolinska University Hospital
      • • Department of Oncology
      • • Department of Clinical Chemistry
      Tukholma, Stockholm, Sweden
    • Università degli Studi G. d'Annunzio Chieti e Pescara
      Chieta, Abruzzo, Italy
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2004
    • Nagoya University
      • Graduate School of Medicine
      Nagoya, Aichi, Japan
  • 1989–2002
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1986–2002
    • Slovak Academy of Sciences
      • Institute of Chemistry
      Bratislava, Bratislavsky Kraj, Slovakia
    • KTH Royal Institute of Technology
      Tukholma, Stockholm, Sweden
    • University of California, Irvine
      • Department of Microbiology & Molecular Genetics
      Irvine, California, United States
  • 2001
    • Netherlands Cancer Institute
      Amsterdamo, North Holland, Netherlands
  • 1999
    • University of Iowa
      • Department of Biochemistry
      Iowa City, Iowa, United States
  • 1996–1999
    • University of Costa Rica
      • Departamento de Bioquímica
      San José, Provincia de San Jose, Costa Rica
  • 1990–1999
    • Autonomous University of Barcelona
      • • Department of Biochemistry and Molecular Biology
      • • Departamento de Química
      Cerdanyola del Vallès, Catalonia, Spain
    • National Institutes of Health
      Maryland, United States
  • 1997
    • RMIT University
      Melbourne, Victoria, Australia
  • 1987–1995
    • University of Karachi
      • Department of Microbiology
      Karachi, Sindh, Pakistan
  • 1994
    • The Rockefeller University
      • Laboratory of Molecular and Cellular Neuroscience
      New York City, NY, United States
    • European Molecular Biology Laboratory
      Heidelburg, Baden-Württemberg, Germany
  • 1993
    • National Defense Medical Center
      • Department of Biochemistry
      Taipei, Taipei, Taiwan
  • 1992–1993
    • University of Gothenburg
      Goeteborg, Västra Götaland, Sweden
  • 1987–1993
    • Harvard Medical School
      • Center for Biochemical and Biophysical Sciences
      Boston, MA, United States
  • 1985–1993
    • Stockholm University
      • Department of Biochemistry and Biophysics
      Tukholma, Stockholm, Sweden
  • 1989–1992
    • University of Barcelona
      • Department of Genetics
      Barcino, Catalonia, Spain
  • 1983–1992
    • H.E.J. Research Institute of Chemistry
      Kurrachee, Sindh, Pakistan
    • Umeå University
      • Department of Medical Biochemistry and Biophysics
      Umeå, Västerbotten, Sweden
  • 1991
    • University of Oslo
      • Department of Chemistry
      Kristiania (historical), Oslo, Norway
  • 1984–1990
    • University of Aberdeen
      • Department of Chemistry
      Aberdeen, SCT, United Kingdom
  • 1988
    • Capio S:t Görans sjukhus
      Tukholma, Stockholm, Sweden
  • 1981
    • Lund University
      Lund, Skåne, Sweden
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 1980
    • University of California, San Diego
      San Diego, California, United States
  • 1978
    • NCI-Frederick
      Фредерик, Maryland, United States
    • Uppsala University
      Uppsala, Uppsala, Sweden